We have previously found, based on immunohistochemical studies of postmortem human brain material, that some types of striatal projection neurons are more vulnerable than others in Huntington's disease (HD), with the vulnerable types being lost in greater abundance during the middle stages of adult onset HD. In order to better characterize the differential loss of striatal projection neurons, we propose to use immunohistochemical techniques on postmortem brain specimens to: 1) examine the patterns of loss in the early and late stages of adult onset HD among the types of projection neurons we have already studied; 2)0 examine the pattern of loss at all stages of adult HD for some additional types of striatal projection neurons and 3) examine the early and late stages of juvenile onset HD to explore the possibility that in this form of HD the loss among striatal projection neurons is nondifferential (which is implied by our preliminary data and the clinical features of this form of HD). Image analysis will be used to quantify the extent of loss in comparison to normals for each project system. These data on differential striatal projection neuron vulnerability in HD will provide important information for two lines of studies in rats, both of which relate to the possible role of excitotoxicity in mediating striatal cell death in HD. In the first line of study, we will determine whether striatal projection neurons and interneurons that are less susceptible in HD possess a greater capacity for buffering intracellular calcium (by means of their content of either parvalbumin or calbindin) and can thereby prevent the deleterious cascade of events that ensues from the high calcium influxes that attend an excitotoxic event. In the second line of work we will examine whether exposure of striatal neurons in vivo (by means of intrastriatal injections) or in vitro (by incubation of cultured striatal neurons) to the endogenous NMDA-receptor specific excitotoxin, quinolinic acid (QA), yields the pattern of differential death of striatal projection neurons and interneurons observed in HD. If so, the results would support the possibility that cell death in HD might be mediated by NMDA receptor mediated exictotoxicity. The proposed studies will help clarify the neural bases of the symptoms observed at each stage of HD and shed light on the pathogenetic mechanisms underlying HD, particularly on the hypothesis that NMDA-receptor mediated excitoxicity might underly HD. The information gained from these various studies could have therapeutic or prophylactic implications for HD gene carriers, as well as for other disorders involving excitotoxin-mediated neuronal degeneration.